Chemotherapy is the main treatment means in traditional cancer treatment. Chemotherapy drugs block cell division non-specifically to cause cell death, and they also destroy the growth of normal human cells greatly while killing tumor cells to bring many adverse reactions. Many people are pessimistic and even give up the treatment because they concern about the serious side effects of chemotherapy. In addition, the chemotherapy for non-small cell lung cancer (NSCLC) is not optimistic due to the drug resistance of chemotherapy drugs, and the extension of the chemotherapy cycle only increases the toxic or side effect, but not the efficacy. At the same time, NSCLC cells are not sensitive to chemotherapy or conventional chemotherapy, and the overall response rate is only about 25%. The five-year survival rate of NSCLC patients is less than 20% due to these reasons.
Among 50%-80% of NSCLC patients, their epidermal growth factor receptors (EGFRs) are over-expressed, causing canceration. There are two main types of EGFR-targeted drugs: one is a small molecule tyrosine kinase inhibitor (TKI) that acts on the intracellular region of the receptor; and the other one is a monoclonal antibody (MAb) that acts on the extracellular region of the receptor. The first-generation EGFR inhibitors that have been used in clinic, such as iressa, erlotinib and lapatinib, have achieved a great success in the treatment of NSCLC, and have improved the five-year survival rate of NSCLC patients. At the same time, compared with the chemotherapy, they have the advantage of not causing side effects such as myelosuppression, nausea and neurotoxicity; however, they are less effective when they are used for treating alone and have obvious side effects such as rash and diarrhea, and the patients have resistance to the drugs after one-year treatment. Research suggested that the mutation at the T790M locus of the EGFR gene is the main cause of drug resistance to such drugs. Clinical case data show that patients' acquired drug resistance of approximately 50% is derived from the mutation at the T790M locus. Further studies confirmed that the mutation at the T790M of the EGFR gene, i.e., the conversion of encoded threonine into methionine, caused the steric hindrance to hinder the binding of the inhibitor to the ATP binding region and ultimately resulted in the loss of activity of the inhibitors. Studies have also shown at present that the mutation at the T790M locus did not directly affect the affinity of the inhibitor to the EGFR, but greatly increased the affinity of the EGFR to ATP, resulting in a relatively significant decrease in the affinity of the inhibitor to the EGFR (the inhibitor was competitively bound with the ATP). The second-generation inhibitors such as afatinib and dacomitinib, superior to the first generation, were characterized by the increase of recognition on EGFR, and can distinguish tumor cells from normal cells, thus reducing the side effects. However, the poor selectivity of these molecules for T790M mutants of EGFR results in lower clinically tolerated doses of drugs. Under the maximum tolerated dose (MTD), the drugs cannot reach an effective concentration in vivo and are ineffective for most drug-resistant patients.
In short, the conventional EGFR-TKI still cannot solve the clinical needs caused by drug resistance, and the conventional drugs are mostly reversible or irreversible EGFR inhibitors with quinazoline or quinolinamine as the basic nucleus, which have poor selectivity on wild-type cells to cause inevitable toxic or side effects. Therefore, new types, especially novel skeletons of compounds are urgently needed in clinic to solve the problems of drug resistance, poor selectivity and the like.